Emergency myelopoiesis distinguishes multisystem inflammatory syndrome in children from pediatric severe COVID-19

Katerina Roznik; Temesgen E Andargie; T Scott Johnston; Oren Gordon; Yi Wang; Nadine Peart Akindele; Deborah Persaud; Annukka A R Antar; Yukari C Manabe; Weiqiang Zhou; Hongkai Ji; Sean Agbor-Enoh; Andrew H Karaba; Elizabeth A Thompson; Andrea L Cox

doi:10.1093/infdis/jiae032

Emergency myelopoiesis distinguishes multisystem inflammatory syndrome in children from pediatric severe COVID-19

J Infect Dis. 2024 Jan 31:jiae032. doi: 10.1093/infdis/jiae032. Online ahead of print.

Authors

Katerina Roznik^{1

2}, Temesgen E Andargie^{3

4}, T Scott Johnston², Oren Gordon^{5

6}, Yi Wang⁷, Nadine Peart Akindele⁶, Deborah Persaud^{1

6}, Annukka A R Antar², Yukari C Manabe², Weiqiang Zhou⁷, Hongkai Ji⁷, Sean Agbor-Enoh^{2

3}, Andrew H Karaba², Elizabeth A Thompson², Andrea L Cox^{1

2}

Affiliations

¹ Johns Hopkins Bloomberg School of Public Health, W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA.
² Johns Hopkins University School of Medicine, Department of Medicine, Division of Infectious Diseases, Baltimore, Maryland, USA.
³ Genomic Research Alliance for Transplantation and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), The National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Biology, Howard University, Washington DC, USA.
⁵ Infectious Diseases Unit, Department of Pediatrics, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
⁶ Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, Maryland, USA.
⁷ Johns Hopkins Bloomberg School of Public Health, Department of Biostatistics, Baltimore, Maryland, USA.

PMID: 38299308
DOI: 10.1093/infdis/jiae032

Abstract

Background: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent SARS-CoV-2 infection, but the underlying immunological mechanisms driving this distinct syndrome are unknown.

Methods: We utilized high dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute COVID-19 (SAC).

Results: Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen presenting cells. IL-27, a cytokine known to drive hematopoietic stem cells towards EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased, and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood.

Conclusions: Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing towards MIS-C, offering potential diagnostic and therapeutic targets.

Keywords: IL-27; MIS-C; cell-free DNA; emergency myelopoiesis; pediatric COVID-19.

Grants and funding

K08 AI156021/AI/NIAID NIH HHS/United States